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Page 11 of 36 J Cancer Metastasis Treat 2019;5:31 I http://dx.doi.org/10.20517/2394-4722.2019.21

14. The histone methyl transferase DOT1L is a key functional partner of estrogen receptor
alpha for regulation of gene transcription in hormone-responsive breast cancer

1
1
1,2
1
1,2
Giovanni Nassa , Annamaria Salvati , Giorgio Giurato , Roberta Tarallo , Francesca Rizzo , Lorenza
3
1
Mautone , Domenico Rocco , Tuula Anneli Nyman , Alessandro Weisz 1
1
1 Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry “Scuola
Medica Salernitana”, University of Salerno, Baronissi, SA 84084, Italy.
2 Genomix4Life S.r.l., University of Salerno, Baronissi, SA 84084, Italy.
3 Proteomics Core Facility, Institute of Clinical Medicine, University of Oslo, Oslo 0315, Norway.
Estrogen Receptor alpha (ERα) is a key mediator of estrogen signaling in hormone-responsive breast
cancer (BC) and target of endocrine therapies, where resistance to treatment is a major problem in clinical
management of these patiens. A better understanding of the molecular mechanisms of ERα actions in
cancer may lead to identification of new therapeutic targets against endocrine terapy-resistant tumors. We
recently identified the epigenetic writer DOT1L (DOT1 Like Histone Lysine Methyltransferase) as novel a
nuclear partner of ERα in hormone-responsive BC cells. To investigate the functional role of this enzyme
in mediating receptor actions in target cell nuclei, physical and functional ERα-DOT1L interaction on
chromatin was mapped by Chromatin Immunoprecipitation coupled to Mass Spectrometry (ChIP-MS) and
Sequencing (ChIP-Seq), transcriptome profiling (RNA-Seq) coupled to gene silencing and pharmacological
inhibition of either protein. Cellular and functional assays were also used to evaluate the impact of the
ERα-DOT1L complex in hormone-responsive BC cell functions. ChIP-MS confirmed co-recruitment of
the two factors on chromatin in a multiprotein complex. Gene expression profiling and Nascent RNA-Seq
before and after DOT1L pharmacological inhibition showed that this enzyme is involved in ERα-mediated
transcriptional regulation of several estrogen responsive genes, including ERα itself. ChIP-Seq mapped
co-occupancy of several chromatin sites by both proteins, including the ERα gene promoter itself. These
results reveal that physical and functional association between ERα and DOT1L is a key molecular event in
hormonal control of BC cell functions, suggesting that this enzyme might represent a potential drug target
against hormone-responsive tumors.

Biography
Dr. Giovanni Nassa completed his PhD at University of Campania “Luigi Vanvitelli” and presently is fixed-
term Researcher (RTDa) of General Pathology at the Department of Medicine, Surgery and Dentistry “SMS”
of the University of Salerno. AIRC Fellow during the early stages of his career, he was also visiting scientist
and FEBS fellow at the Institute of Biotechnology and Biomedicum of the University of Helsinki. He
published more than 30 papers in international peer-review journals, with research mainly focusing on the
epigenetic mechanisms underlying hormone-responsive breast cancer pathogenesis and loss of response to
endocrine therapy during progression.

15. IL-4 as a potential treatment for cancer-induced muscle wasting

Paola Costelli

Department of Clinical and Biological Sciences, University of Turin, Turin 10126, Italy.

Skeletal muscle wasting, one of the most relevant features of cancer cachexia, is mainly associated with
marked alterations of protein turnover. Few years ago the observation that also myogenesis is impaired in